This invention relates to a process for the optical resolution of racemic 3-(p-chlorophenyl)-glutaramide (GAN) into its R and S isomers, and to the use of the R isomer for the production of R-baclofen or the use of the S isomer for the production of S-baclofen.
The biological activity and physical properties of racemic baclofen are well documented in the literature.sup.1,2. Further extensive pharmacological tests have concluded that the biological activity of the drug resides with the R-enantiomer (R-baclofen).sup.3. These selective activities have led to extensive research concerning methods of separating the optical isomers of baclofen. Several methods of resolution have since appeared in the literature. These are mainly chromatographic separations.sup.4-9, making use of either bonded chiral stationary phases, or mobile phases with chiral modifiers. Other methods include asymmetric syntheses.sup.10-12 as well as a chemoenzymatic synthesis.sup.13.
As is apparent from the literature, most chromatographic separations involve precolumn derivatization implying some form of protection and subsequent deprotection. Where the formation of covalent diastereomers is not necessary, the columns used involved either relatively expensive chiral stationary phases or chiral modifiers in the mobile phase. The asymmetric syntheses are mostly time consuming multistep reactions with relatively low yields.
The compound .alpha.-methylbenzylamine (MBA) is well known as a resolving agent in both covalent and dissociable diastereomer techniques.sup.16. MBA is a strong base widely used for resolution of acidic racemates and in particular carboxylic acids. Examples are MBA mandelate.sup.17, MBA phenylbutyrate.sup.18 and MBA hydrotropate.sup.19 salts. Concerning drug resolution, a good example is the early separation of the antibacterial fosfomycin.sup.20.